Rheumatoid arthritis (RA) is the most common inflammatory arthritis, affecting approximately 1% of the population world wide (Wolfe, F., “The epidemiology of drug treatment failure in rheumatoid arthritis”, Baillieres Clin. Rheumatol., 9(4):619-632 (November 1995)). Women are 2-3 times more likely to develop disease compared to men, with a peak incidence between the fourth and sixth decades of life (Hochberg, M. C. et al., “Epidemiology of rheumatoid arthritis: update”, Epidemiol. Rev., 12:247-252 (1990); Markenson, J. A., “Worldwide trends in the socioeconomic impact and long-term prognosis of rheumatoid arthritis”, Semin. Arthritis Rheum., 21(2 Suppl. 1):4-12 (October 1991); Spector, T. D., “Rheumatoid arthritis”, Rheum. Dis. Clin. North Am., 16(3):513-537 (August 1990); and Zvaifler, N. J., “Etiology and pathogenesis of rheumatoid arthritis”, in Arthritis and Allied Conditions, McCarty, D. J., Koopman, W. J., eds. Philadelphia: Lea & Febiger, 723-736 (1993)). While RA is recognized clinically because of the severe inflammation affecting the synovial joints, it is also a systemic disease with frequent extra-articular manifestations. The natural history of RA is unfortunately characterized by joint destruction, impaired physical function and poor health related quality of life.
There is increasing scientific evidence that joint destruction occurs early in RA. Over 90% of subjects have evidence of joint damage by conventional radiography within two years after the diagnosis of RA (Emery, P., “The Optimal Management of Early Rheumatoid Disease: The Key to Preventing Disability”, Br. J. Rheum., 33:765-768 (1994)). Joint damage can be detected within weeks of the onset of symptoms using more sensitive techniques such as MRI or ultrasound (McGonagle, D. et al., “The relationship between synovitis and bone changes in early untreated rheumatoid arthritis”, Arthritis Rheum., 42:1706-1711 (1999) and Wakefield, R. J. et al., “The value of sonography in the detection of bone erosion in patients with rheumatoid arthritis: A comparative study with conventional radiography”, Arthritis Rheum., 43:2761-2770 (2000)). These findings have created an increasing need for therapies which can effectively inhibit the inflammatory processes which cause bone and cartilage loss early on in RA and have placed increasing emphasis on earlier diagnosis and treatment of RA.
However, the 1987 American Rheumatism Association (ARA) criteria for RA are less sensitive and specific when applied to subjects with early inflammatory arthritis compared to subjects with more established disease. Subjects with early inflammatory arthritis may have oligoarthritis rather than polyarthritis, may have symptoms of arthritis for less than six weeks or may initially lack rheumatoid factor, rheumatoid nodules or erosions on conventional radiography (Van Gaalen, F. A. et al., “Autoantibodies to Cyclic Citrullinated Peptides Predict Progression to Rheumatoid Arthritis in Patients with Undifferentiated Arthritis”, Arthritis Rheum., 50(3):709-715 (2004)). As a result, these subjects often fail to meet the 1987 diagnostic criteria for RA (or any other rheumatic disease) early on in the disease process. These subjects are then diagnosed with undifferentiated arthritis (UA) by the process of exclusion. Approximately 40% of subjects referred to specialized tertiary care centers designed for the diagnosis and management of early inflammatory arthritis do not meet diagnostic criteria for RA or any other rheumatic disease (Van Gaalen, F. A. et al., “Autoantibodies to Cyclic Citrullinated Peptides Predict Progression to Rheumatoid Arthritis in Patients with Undifferentiated Arthritis”, Arthritis Rheum., 50(3):709-715 (2004)). Therefore undifferentiated arthritis is a common clinical entity.
The normal synovium is a tissue that surrounds and separates joint spaces. The lining layer of cells, composed of macrophage-like and fibroblast-like synoviocytes, overlays a thin connective tissue stroma containing sparse numbers of dendritic cells, fibroblasts, mast cells and vascular structures (Konttinen, Y. T. et al., “Characterization of the immunocompetent cells of rheumatoid synovium from tissue sections and eluates”, Arthritis Rheum., 24(1):71-79 (January 1981)).
In RA, the synovial tissue becomes markedly thickened and swollen. As the disease progresses, there is gradual proliferation and recruitment of synoviocytes, as well as recruitment of inflammatory cells into the synovium (Konttinen, Y. T. et al., “Characterization of the immunocompetent cells of rheumatoid synovium from tissue sections and eluates”, Arthritis Rheum., 24(1):71-79 (January 1981)). Up to 50% of the infiltrating leukocytes in the synovium are T-lymphocytes, primarily CD4+ T cells with an activated/memory phenotype (Konttinen, Y. T. et al., “Characterization of the immunocompetent cells of rheumatoid synovium from tissue sections and eluates”, Arthritis Rheum., 24(1):71-79 (January 1981); Forre, O. et al., “Augmented numbers of HLA-DR-positive T lymphocytes in the synovial fluid and synovial tissue of subjects with rheumatoid arthritis and juvenile rheumatoid arthritis: in vivo-activated T lymphocytes are potent stimulators in the mixed lymphocyte reaction”, Scand. J. Immunol., 15(2):227-231 (February 1982); Van-Boxel, J. A. et al., “Predominantly T-cell infiltrate in rheumatoid synovial membranes”, N. Engl. J. Med., 293(11):517-520 (September 1975); Kidd, B. L. et al., “Immunohistological features of synovitis in ankylosing spondylitis: a comparison with rheumatoid arthritis”, Ann. Rheum. Dis., 48(2):92-98 (February 1989); Cush, J. J. et al., “Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from subjects with rheumatoid arthritis”, Arthritis Rheum., 31(10):230-238 (October 1988); Laffon, A. et al., “Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis”, J. Clin. Invest., 88(2):546-552 (August 1991); and Klareskog, L. et al., “Relationship between HLA DR expressing cells and T lymphocytes of different subsets in rheumatoid synovial tissue”, Scand. J. Immunol., 15(5):501-507 (May 1981)). Cells of monocyte/macrophage origin also become prominent in the rheumatoid synovium, accounting for up to 20% of cells, and they too exhibit an activated phenotype (Firestein, G. S. et al., “How important are T cells in chronic rheumatoid synovitis?” Arthritis Rheum., 33(6):768-773 (June 1990) and Firestein, G. S. et al., “Quantitative analysis of cytokine gene expression in rheumatoid”, J. Immunol., 144(9):3347-3353 (May 1, 1990)). Monocyte/macrophage-like cells in the rheumatoid synovium produce an array of pro-inflammatory molecules, including the cytokines IL-1, TNF-α, IL-6, GM-CSF as well as proteolytic enzymes including collagenases and matrix metalloproteinases. B-cells, plasma cells and neutrophils account for less than 5% of cells in the rheumatoid synovium, although neutrophils are prominent in the synovial fluid (Konttinen, Y. T. et al., “Characterization of the immunocompetent cells of rheumatoid synovium from tissue sections and eluates”, Arthritis Rheum., 24(1):71-79 (January 1981); Forre, O. et al., “Augmented numbers of HLA-DR-positive T lymphocytes in the synovial fluid and synovial tissue of subjects with rheumatoid arthritis and juvenile rheumatoid arthritis: in vivo-activated T lymphocytes are potent stimulators in the mixed lymphocyte reaction”, Scand. J. Immunol., 15(2):227-231 (February 1982); and Firestein, G. S. et al., “Quantitative analysis of cytokine gene expression in rheumatoid”, J. Immunol., 144(9):3347-3353 (May 1, 1990)).
As synovial proliferation and inflammation advances, the expanding mass of vascular, inflammatory synovial tissue is termed pannus. Pannus is responsible for invading articular cartilage and destroying bone. The products of activated T cells are felt to be the driving factors behind the formation and expansion of pannus (Zvaifler, N. J. et al., “Alternative models of joint destruction in rheumatoid arthritis”, Arthritis Rheum., 37(6):783-789 (June 1994)).
The monocyte/macrophage-like cells and dendritic cells in the rheumatoid synovium express both class II MHC as well as costimulatory molecules such as CD80 (B7-1)/CD86 (B7-2), and presumably function as antigen presenting cells (Balsa, A. et al., “Differential expression of the costimulatory molecules B7.1 (CD80) and B7.2 (CD86) in rheumatoid synovial tissue”, Br. J. Rheumatol., 35(1):33-37 (January 1996); Liu, M. F. et al., “The presence of costimulatory molecules CD86 and CD28 in rheumatoid arthritis synovium”, Arthritis Rheum., 39(1):110-114 (January 1996); Ranheim, E. A. et al., “Elevated expression of CD80 (B7/BB1) and other accessory molecules on synovial fluid mononuclear cell subsets in rheumatoid arthritis”, Arthritis Rheum., 37(11):1637-1646 (November 1994); Sfikakis, P. P. et al., “Expression of CD28, CTLA4, CD80, and CD86 molecules in subjects with autoimmune rheumatic diseases: implications for immunotherapy”, Clin. Immunol. Immunopathol., 83(3):195-198 (June 1997); and Thomas, R. et al., “Functional differentiation of dendritic cells in rheumatoid arthritis: role of CD86 in the synovium”, J. Immunol., 156(8):3074-3086 (Apr. 15, 1996)). Activated CD4+ T cells expressing CD28 are prominent infiltrating cell types in the rheumatoid synovium and commonly are found adjacent to cells that express class II MHC and costimulatory molecules. This suggests an important role for T cell activation/costimulation in the pathogenesis of synovial inflammation. This is consistent with the experimental observation that activated T cells, either through cell to cell contact with synoviocytes and osteoclasts or by the elaboration of secreted cytokines, are important factors in driving synovitis and bone destruction in RA. Taken together, these observations suggest that activated T cells and the costimulatory signals delivered through CD28 play a key role in driving the immunopathology of RA.
The approach to the treatment of RA has evolved towards initiating Disease Modifying Anti-Rheumatic Drug (DMARD) therapy earlier following diagnosis with subsequent optimization of drug therapy in order to have a greater beneficial impact on disease outcome (Redlich, K. et al., “Rheumatoid Arthritis Therapy After Tumor Necrosis Factor and Interleukin-1 Blockade”, Arthritis Rheum., 40(12):3308-3319 (2003)). However, no standard of care exists for the treatment of patients with UA (Harrison, B. J. et al., “Natural remission in inflammatory polyarthritis: issues of definition and prediction,” Br. J. Rheumatol., 35:1096-1100 (1996)). This is largely due to the inability of the clinician to accurately determine the prognosis of these subjects and their risk for the development of RA based upon commonly used clinical characteristics at presentation. Undifferentiated arthritis may remit spontaneously, progress to a differentiated rheumatic disease such as RA or remain undifferentiated (Quinn, M. A. et al., “Evaluation and management of early inflammatory polyarthritis”, Rheumatology, Third Edition, MOSBY (Elsevier Limited), 885-891 (2003)). DMARDs are usually not initiated at onset in subjects with UA due to the uncertainty about the prognosis. Instead NSAIDs are traditionally the first drugs to be employed followed by oral corticosteroids. DMARDs are usually used when the symptoms and signs of arthritis are refractory to the first two types of intervention. Hence a “pyramidal” approach has been traditionally employed (Harrison, B. J. et al., “Natural remission in inflammatory polyarthritis: issues of definition and prediction”, Br. J. Rheumatol., 35:1096-1100 (1996)). Unfortunately, however, this approach may permit the patient to develop joint damage and destruction before the initiation of potentially disease modifying therapy.
No approved anti-rheumatic therapy has been demonstrated to fundamentally alter the course of undifferentiated arthritis and prevent the development of RA. An agent targeting TNF alpha, infliximab, has been studied in a clinical trial targeting prevention/remission of early RA after a short course of TNF antagonist therapy. However, published data demonstrate that a 6 month course of TNF antagonist therapy does not prevent the progression of UA to RA (Saleem, B. et al., Rheumatology, Academic Unit of Musculoskeletal Disease, Leeds, United Kingdom, Ann. Rheum. Dis., 66(Suppl. II):186 (2007)).
Clearly, there is a need for a treatment that can offer subjects with undifferentiated arthritis at high risk for the development of RA the opportunity to fundamentally alter the course of their disease by selectively targeting T cell activation and preventing the development of RA.